Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to novel pyridazinone derivatives having cardiotonic activity, to pharmaceutically acceptable acid addition salts thereof, and to pharmaceutical preparations containing them.
• Pyridazinone ring compounds are known which exhibit cardiotonic activity, for example:
• Pyridone ring compounds are also known to exhibit cardiotonic activity, for example:
• Such cardiotonics are used in the treatment of chronic cardiac insufficiency, but are so far somewhat unsatisfactory both in effectiveness and duration.
• the alkyl moiety in the lower alkyl, lower alkoxycarbonylamino, lower alkoxyl and lower alkylthio groups is a straight-chain or branched alkyl group having 1 to 8 carbon atoms.
• examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl and isooctyl.
• the substituted alkyl group contains 1 to 3 substituents, which may be the same or differnt, such as hydroxyl, lower alkoxyl, carboxyl, lower alkoxycarbonyl, amino, mono- or di-alkyl-substituted amino, nitrogen-containing aliphatic heterocyclic group, nitro and halogen; the alkyl moiety in the lower alkoxyl, lower alkoxycarbonyl, mono- or di-alkyl-substituted amino groups is a straight-chain or branched alkyl group containing 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, the nitrogen-containing aliphatic heterocyclic group includes pyrrolidinyl, piperidino, piperazinyl, N-methylpiperazinyl, morpholino, thiomorpholino, homopiperazinyl and N-
• the alicyclic alkyl group has 3 to 8 carbon atoms, and includes cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl.
• the lower alkenyl represents an alkenyl group having 2 to 6 carbon atoms, and includes vinyl, allyl, propenyl, butenyl and hexenyl.
• the aralkyl group has 7 to 15 carbon atoms, and includes benzyl, phenethyl and benzhydril.
• the aryl group has 6 to 10 carbon atoms, and includes phenyl and naphthyl.
• the aryl group and the aromatic ring moiety of the aralkyl group contain 1 to 2 substituents, which may be the same or different, such as hydroxyl, lower alkoxyl, amino, mono-or di-alkyl-substituted amino, nitro and halogen; and the lower alkoxyl, mono- or di-alkyl-substituted amino and halogen respectively represent the same as in the above definitions of the substituents in the substituted alkyl group.
• the nitrogen-containing heterocyclic group formed by R, together with R 2 includes the same groups as the nitrogen-containing aliphatic heterocyclic group.
• Compound (I) shows tautomerism.
• Compound (I) wherein R 2a is hydrogen is represented by the following tautomers. All the tautomers of Compound (I) are included within the scope of the present invention.
• the pharmaceutically acceptable acid addition salts of Compound (I) include salts with various inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and phosphate, and salts with various organic acids such as formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxalate, aspartate, methanesulfonate and benzenesulfonate.
• various inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and phosphate
• organic acids such as formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxalate, aspartate, methanesulfonate and benzenesulfonate.
• Compounds (I) can be produced from Compounds (Ila-c) which can be prepared by the following reaction steps:
• R 3 and R4 have the same meanings as defined above;
• R 7 represents alkyl or aryl; and Hal represents halogen.
• the alkyl in the definition of R 7 represents an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl; the aryl represents phenyl, etc.; and halogen represented by Hal is chlorine, bromine, iodine, etc.
• Compound (III) [J. Org. Chem., 38, 4044 (1973), etc.] is allowed to react with fuming nitric acid to obtain the nitro (IV).
• Compound (IV) is allowed to react with hydrazine to obtain the cyclized pyridazinone (V), which is then subjected to reaction with copper cyanide to obtain the cyano (VI).
• Compound (VI) is then reduced to obtain Compound (Ila).
• Compound (llb) can be obtained by allowing Compound (Ila) to react with an orthoester.
• Compound (Ilc) can be obtained by allowing Compound (Ila) to react with a halogenated formic acid ester.
• R 2a , R 3 and R 4 have the same meanings as defined above.
• Compound (la) can be produced by subjecting Compound (Ilb) to reaction with Compound (Vlla) of the following formula: R 2a NH 2 (Vlla) (in which R 2a has the same meaning as defined above).
• Compound (Vlla) is used preferably at least in an equivalent amount based on Compound (Ilb), and may be used in large excess in the case where it serves also as a solvent.
• Compound (Vlla) in the form of an acid addition salt.
• the reaction is carried out preferably in the presence of a base at least in an equivalent amount based on Compound (Vlla).
• a base as the acid addition salt, those mentioned above as the acid addition salts of Compound (I) may be used.
• hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, alkoxides such as sodium methoxide and potassium ethoxide, amines such as triethylamine and pyridine, etc. may be used.
• the reaction may be carried out without using any solvent, or in a solvent inert to the reaction.
• a solvent water, alcohols such as methanol and ethanol, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, halogenated hydrocarbons such as dichloromethane and chloroform, etc. may be used.
• the reaction is carried out at a temperature between 0° C and the boiling point of the solvent used and is completed in 10 minutes to 12 hours.
• R 2a and R 3 have the same meanings as defined above.
• Compound (laa) can be obtained in a similar manner as in process A using Compound (Vila) and Compound (Ilc) in place of Compound (Ilb).
• the leaving group represented by L includes mercapto groups, halogen atoms such as chlorine and bromine, alkoxyl groups such as methoxy and ethoxy, alkylthio groups such as methylthio and ethylthio, arylthio groups such as phenylthio, alkylsulfinyl groups such as methylsulfinyl and ethylsulfinyl, arylsulfinyl groups such as phenylsulfinyl, lower alkylsulfonyl groups such as methylsulfonyl, trifluoromethylsulfonyl and ethylsulfonyl, arylsulfonyl groups such as phenylsulfonyl and p-toluenesulfonyl, etc.
• Compound (Vllb) is used in an amount ranging from an equivalent amount to a large excess based on Compound (VIII). If desired, tertiary amines such as triethylamine may be used in order to accelerate the reaction.
• the reaction may be carried out without using any solvent or in a suitable solvent.
• a suitable solvent water, alcohols such as methanol and ethanol, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, etc. can be preferably used.
• the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, and is completed in 10 minutes to 24 hours.
• the starting material, Compound (VIII), can be prepared by Process H or J shown below, or by subjecting the compounds obtained by Process H or J to oxidation, halogenation, etc. in a conventional manner.
• R 2a , R 3 and R 4 have the same meanings as defined above.
• Compound (lba) can be obtained by treating Compound (la) which is obtained by Process A with a base.
• reaction solvent water, alcohols such as methanol and ethanol, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, etc. can be preferably used.
• the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, and is completed in 10 minutes to 24 hours.
• R 3 and R 4 have the same meanings as defined above; and R 8 represents lower alkyl.
• the lower alkyl group represented by R 8 has the same meaning as in the definition of the lower alkyl group in formula (I).
• Compound (Ibb) can be obtained by allowing Compound (Ib) wherein X-Y is
• the base those mentioned in Process A may be used.
• the solvent dimethylformamide, halogenated hydrocarbons such as dichloromethane and chloroform, etc. can be used.
• a base such as pyridine and triethylamine also as the solvent. The reaction is carried out at 0 to 100 °C and is completed in 10 minutes to 12 hours.
• R 3 and R 4 have the same meanings as defined above.
• Compound (Ic) can be obtained by subjecting Compound (Ilb) to reaction with hydrogen sulfide in a basic solvent such as pyridine and triethylamine or in a mixture of such a basic solvent and another solvent.
• the reaction is carried out by introducing hydrogen sulfide gas into the solution of Compound (Ilb) at a temperature between 0°C and the boiling point of the solvent used, and is completed in 10 minutes to 3 hours.
• Compound (Ica) can be obtained in a similar manner as in Process F using Compound (Ila) and carbon disulfide in place of Compound (llb) and hydrogen sulfide, respectively.
• R 3 , R 4 and Rs have the same meanings as defined above.
• Compound (Id) can be obtained by allowing Compound (Ic) which can be prepared by Process F to react with an alkylating agent such as halogenated alkyl and diazoalkane in the presence of a base.
• an alkylating agent such as halogenated alkyl and diazoalkane
• sodium hydroxide potassium carbonate, diazabicycloundecene (DBU), triethylamine, pyridine, dimethylaminopyridine, sodium hydride, etc. may be used.
• DBU diazabicycloundecene
• the reaction is carried out in a solvent inert to the reaction.
• the inert solvent includes water, alcohols such as methanol and ethanol, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, halogenated hydrocarbons such as dichloromethane and chloroform, etc.
• the reaction is carried out at a temperature between 0°C and the boiling point of the solvent used, and is completed in 10 minutes to 12 hours.
• R 3 , R 4 and Rs have the same meanings as defined above.
• Compound (le) can be obtained in a similar manner as in Process H using Compound (X) of the following formula: HaICH(COOR s ) 2 ( X) (wherein Rs and Hal have the same meanings as defined above) as the alkylating agent.
• R 3 and R 8 have the same meanings as defined above; and R 4a represents the same lower alkyl groups as those in the definition of R 4 .
• the suitable acylating agent includes acid anhydrides, acid halides, etc. of the corresponding carboxylic acids.
• R 3 , R 4 . and Rs have the same meanings as defined above.
• Compound (Ig) can be obtained by treating Compound (le) which can be obtained by Process I with triphenylphosphine in the presence of a base.
• the reaction is carried out under the same conditions as in Process H using the same base and reaction solvent.
• R 3 and R 4 have the same meanings as defined above.
• Compound (Ih) can be obtained by subjecting Compound (Ig) which can be obtained by Process K to saponification under alkaline conditions.
• the reaction is carried out in an aqueous solution of an alkali such as sodium hydroxide and potassium hydroxide or in a solvent mixture of such solution and an alcohol (e.g., methanol and ethanol) at a temperature between room temperature and the boiling point of the solvent used, and is completed in 10 minutes to 12 hours.
• an alkali such as sodium hydroxide and potassium hydroxide
• a solvent mixture of such solution and an alcohol e.g., methanol and ethanol
• R 3 and R4 have the same meanings as defined above.
• Compound (li) can be obtained by subjecting Compound (Id) which can be obtained by Process H to reduction (desulfurization).
• Raney nickel is preferably used as the reducing agent.
• the reaction is carried out in a solvent such as water, alcohols (e.g., methanol and ethanol) and dimethylformamide at a temperature between room temperature and the boiling point of the solvent used, and is completed in 30 minutes to 12 hours.
• a solvent such as water, alcohols (e.g., methanol and ethanol) and dimethylformamide at a temperature between room temperature and the boiling point of the solvent used, and is completed in 30 minutes to 12 hours.
• R 3 and R 4 have the same meanings as defined above.
• Compound (Ij) can be obtained by oxidizing Compound (li) which can be obtained by Process M.
• manganese dioxide manganese dioxide, chromic acid, hydrogen peroxide, etc. are suitable.
• the reaction is carried out at 0° C to 50° C and completed in 10 minutes to 12 hours.
• R 3 , R 4 and.n have the same meanings as defined above.
• Compound (Ik) can be obtained from Compound (Ilb) and Compound (Vllc) of the following formula: H 2 N(CH 2 ) n NH 2 (VIIc) (wherein n has the same meaning as defined above) or an acid addition salt thereof in a similar manner as in Process A.
• Compound (Ik) wherein R4 is hydroxyl can also be obtained by using Compound (Ilc) in place of Compound (Ilb).
• R 3 , R 4 and Rs have the same meanings as defined above.
• Compound (Il) can be obtained by allowing Compound (la) wherein X-Y is prepared by Process A to react with Carboxylic Acid (XII) of the following formula: R 6 COOH (XII) (wherein Rs has the same meaning as defined above) or a reactive derivative thereof (e.g., esters, orthoesters and acid halides).
• Compound (1m) can be obtained in a similar manner as in process H from Compound (Ica) wherein R 4 is a mercapto group which can be obtained by Process G.
• Compound (In) can be obtained by oxidizing the alkylthio group of Compound (Im) which is obtainable by Process Q with a suitable oxidizing agent and then allowing the oxidized product to react with Amine (Vllb).
• the suitable oxidizing agent includes potassium permanganate, hydrogen peroxide, m-chloroperbenzoic acid, etc.
• the reaction of the oxidized product with Amine (Vllb) can be carried out in a similar manner as in Process C.
• Process for producing Compound (I), as well as processes for producing Compounds (Ila-c) which are starting compounds, are not limited to those described above.
• the ring closure utilizing hydrazine can be carried out as the last step in each process. It is possible to first prepare Precursors (Xllla-c) from Compound (IV) in accordance with the processes described above.
• the intermediates and the desired products in the processes described above can be isolated and purified by the purification methods conventionally employed in the organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization and various kinds of chromatography.
• the intermediates can be employed in the next step without substantial purification.
• the anesthesia was sustained by means of inhalation of halothane and dinitrogen oxide.
• a muscle relaxant pancronium bromide
• pancronium bromide pancronium bromide
• test compounds were dissolved in PEG-400 and administered through the right forelimb vein (i.v.) at a dose shown in Table 2.
• mice Three dd strain male mice weighing 20 ⁇ 1 g were used for each group and the test compounds were orally administered to the mice. Seven days after the administration, the mice were checked whether still alive or not in order to determine the minimal lethal dose of the compounds.
• Cardiotonics containing Compound (I) or pharmaceutically acceptable acid addition salts thereof can be prepared in any form of conventionally employed formulations, e.g., tablets, capsules, syrups, injections, drops and suppositories, and can be administered either orally or non-orally, e.g., by means of intramuscular injection, intravenous injection, intraarterial injection, drip and insertion of suppositories into rectum.
• Such formulations for oral or non-oral administration can be prepared by known methods and may contain various excipients, lubricants, binders, disintegrators, suspending agents, osmotic pressure regulators, emulsifying agents, and the like.
• Examples of the carriers which can be used in the formulations are water, distilled water for injection, physiological saline solution, glucose, fructose, sucrose, mannitol, lactose, starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogenphosphate, magnesium stearate, urea, silicone resins, sorbitan fatty acid ester, and glycerol fatty acid ester.
• the dose varies depending on mode of administration, age, body weight and conditions of a patient, etc.
• oral administration it is usually in the range of 0.05 to 200 mg/60 kg/day.
• the compounds can be administered at a rate of 0.01 to 5 ⁇ g/kg/min. and at a daily dose within the limit of the above daily dose for oral administration.
• the desired compounds were obtained in a similar manner as in Example 1, employing the conditions shown in Table 4-1.
• the crude products obtained were purified, where necessary, by means of the above- mentioned chromatography, recrystallization, etc.
• Example 11 Compound 11 (0.34 g) obtained in Example 11 was dissolved with heating in 10 ml of 1 N hydrochloric acid. The solution was cooled, and the crystals precipitated were collected by filtration and dried to give 0.21 g (54%) of 6-(4-aminoquinazolin-7-yl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone monohydrochloride monohydrate (Compound 11 ).
• the desired compounds were obtained in a similar manner as in Example 13, employing the conditions shown in Table 4-2.
• the crude products obtained were purified, where necessary, by means of the above- mentioned chromatography, recrystallization, etc.
• the desired compounds were obtained in a similar manner as in Example 20, employing the conditions shown in Table 4-3.
• the crude products obtained were purified, where necessary, by means of the above- mentioned chromatography, recrystallization, etc.
• Example 61 The same procedure as in Example 62 was repeated, except that 40% n-propylamine solution in methanol was used in place of 40% methylamine solution in methanol. As a result, 0.12 g (39%) of 4,5-dihydro-5-methyl-6-(2-methylthio-4-n-propylaminoquinazolin-7-yl)-3(2H)-pyridazinone (Compound 61) was obtained.
• Example 63 Compound 61 (0.40 g) obtained in Example 63 was dissolved in 20 ml of 50% acetic acid, and then 0.50 g of potassium permanganate was added to the solution at 5 to 10° C, followed by stirring for 10 minutes. After 100 ml of water was added, the mixture was extracted 5 times with 20 ml of chloroform. The combined chloroform layer was added to 40% methylamine solution in methanol and the mixture was stirred at 60. C for 10 hours. The resulting mixture was concentrated and subjected to partition between water and chloroform. The organic layer was dried and then concentrated.
• Example 67 The same procedure as in Example 68 was repeated, except that 1 ml of 40% methylamine solution in methanol was added dropwise instead of the introduction of ammonia gas. As a result, 0.21 g (74%) of 4,5-dihydro-6-(1,2,3,4-tetrahydro-4-imino-3-methyl-2-oxo-1H,3H-quinazolin-7-yl)-5-methyl-3(2H)-pyridazinone (Compound 67) was obtained.
• Example 68 The same procedure as in Example 68 was repeated, except that 1 ml of ethylenediamine was added instead of the introduction of ammonia gas. As a result, 0.20 g (67%) of 4,5-dihydro-6-(2,3-dihydro-5-oxo-6H-imidazo[1,2-c]-quinazolin-8-yl)-S-methyl-3(2H)-pyridazinone (Compound 68) was obtained.
• Example 18 The same procedure as in Example 18 was repeated, except that 0.67 g of Compound k obtained in Reference Example 11 was used instead of Compound e. As a result, 0.49 g (77%) of 4,5-dihydro-6-(4-mercaptoquinazolin-7-yl)-3(2H)-pyridazinone (Compound 76) was obtained.
• Example 77 The same procedure as in Example 19 was repeated, except that 0.10 g of Compound 76 obtained in Example 77 was used instead of Compound 56. As a result, 0.10 g (95%) of 4,5-dihydro-6-(4-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (Compound 77) was obtained.
• Example 78 The same procedure as in Example 36 was repeated, except that 0.29 g of Compound 77 prepared in Example 78 was used instead of Compound 57. As a result, 0.06 g (17%) of 6-(4-benzylaminoquinazolin-7-yl)-4,5-dihydro-3(2H)-pyridazinone (Compound 78) was obtained.

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